Indole derivatives in the treatment of skeletal muscle fatigability

ABSTRACT

Skeletal muscle fatigability is treated by administration of a composition containing a skeletal muscle stimulant which is a derivative of indole-3-acetic acid or of indole-3ylmethyltetrazole.

United States Patent Share et al.

[1 1 3,689,657 1 Sept. 5, 1972 INDOLE DERIVATIVES IN THE TREATMENT OF SKELETAL MUSCLE FATIGABILITY Inventors: Nathan Norman Share, 5826 Hudson Ave., Cote St. Luc, Montreal 268, Quebec; Cyril Stephen McFarlane, 2157 Pauline St., Ville Lasalle, Montreal 660, Quebec, both of Canada Filed: Nov. 23, 1970 Appl. No.: 92,299

Foreign Application Priority Data Feb. 3, 1970 Canada ..O73876 US. Cl ..424/274, 424/269 Int. Cl. ..A6lk 27/00 [58] Field of Search ..424/274 [56] References Cited OTHER PUBLICATIONS Walton et al. J. of Med. Chem., Vol. 8, pp. 204- 208 (1965).

Primary Examiner-Stanley J. Friedman AttorneyWilliam H. Nicholson, Harry E. Westlake and l. Louis Wolk [57] ABSTRACT Skeletal muscle fatigability is treated by administration of a composition containing a skeletal muscle stimulant which is a derivative of indole-3-acetic acid or of indole-3-ylmethyltetrazole.

10 Claims, No Drawings INDOLE DERIVATIVES IN THE TREATMENT OF SKELETAL MUSCLE FATIGABILITY formula, (I).

CHZR

. YLMMWW 4... wherein R represents 1. -COZ, wherein Z represents a. hydroxyl,

b. lower alkoxy of from one to about eight carbon atoms, either straight or branch chained and.

either unsubstituted or substituted with i. di(lower alkyl)aminomethyl, wherein the lower alkyl groups have from one to about three carbon atoms, such as methyl, ethyl and P py ii. hydroxy,

iii. phenyl, either unsubstituted or substituted with nitro, halo such as chloro, bromo or fluoro, or lower alkyl of one to about three carbon atoms,

iv. lower alkoxy of from one to about three carbon atoms,

. phenoxy, either unsubstituted or substituted with nitro, halo such as fluoro, chloro or bromo, or lower alkyl of from one to about three carbon atoms,

2. tetrazol-S-yl.

R represents 1. hydrogen,

2. lower alkyl of one to about three carbons,

3. lower. alkenyl of from three to about five carbon atoms, such as allyl, butenyl and the like;

R represents 1. lower alkyl of one to about eight carbon atoms,

either straight or branch chained and either unsubstituted or substituted with a. lower alkoxy of one to about three carbons,

b. lower alkylthio of one to about three carbons, c. halo, such as chloro, bromo, fluoro, dichloro,

' trichloro, or trifluoro,

2. lower alkylcarbonyl, wherein the lower alkyl group has from one to about five carbon atoms;

R represents 1. hydrogen,

2. lower alkyl of one to about three carbon atoms, either unsubstituted or substituted with halo or lower alkoxy of one to about three carbon atoms,

3. nitro,

4. halo such as chloro, bromo or fluoro.

The active agents of the method of this invention have been found in standard laboratory animals to produce myotonic symptoms consisting of temporary rigid extension of the legs when the animal is disturbed. The overt appearance is readily distinguishable from convulsions caused by central stimulation. This stimulation of striated muscle is useful in the treatment of disease entities characterized by progressive fatigability of the muscles such as myasthenia gravis.

Present day therapy for myasthenia gravis generally involves a class of agents termed acetylcholinesterase inhibitors and/or skeletal muscle facilitators. These substances often exhibit side effects such as extreme salivation, involuntary defecation and urination, sweating, lacrimation, bradycardia and hypotension. They have a relatively low therapeutic index and are not always effective. The compounds of the novel method of this invention on the other hand operate through a mechanism of .action different from that of the acetylcholinesterase inhibitors and fail to produce any of the adverse side-effects described above in experimental animals, and have a much higher therapeutic index. They have further been shown to facilitate the activity of acetylcholinesterase inhibitors and therefore may also be used in combination with them to reduce their toxicity.

Treatment with the active agents of this invention can be orally in the form of powders, granules, wafers, tablets, capsules or pills, or by injection intravenously, or intraperitoneally in suspension or in solution. Where Z is hydroxyl they can be administered as a pharmaceutically acceptable salt, such as an alkali metal salt, preferably the potassium or sodium salt. The dose is from 1 to about 50 mgs./kg./day either singly or on a multidose regimen depending on the severity of the disorder and the discretion of the physician.

The indole skeleton of the active compounds of this invention is prepared by standard chemical synthetic procedures well known in the art and are represented by the following reaction sequences:

III

wherein R, and R are as previously defined, and R is other than chloro-, bromo-, dichloroor trichlorolower alkyl.

When R is one of the polyhalogenated alkyls excepted from Method A above an alternate route to compound III is required in as much as the halogen group will not survive the very basic conditions provided by sodamide.

The alternate route to Compound III is represented by the following reaction sequence:

METHOD B IV III unine'i an" The diazomethyl ketone (V), and an approximately equimolar amount of an acid catalyst such as boron trifluoride etherate or the hydrobromide salt of the aniline (IV) are mixed and an excess of the aniline (IV) is added. The mixture is then heated to 175200 C. for from 10 minutes to about 5 hours. The cooled mixture is neutralized and the excess aniline reactant is separated by steam distillation or by extraction from ether solution with dilute acid. The product is then iso- METHOD C I ECHO CH2N(CH3)2 HN(CH3)2 2 N R2 N R 1& 1&1

III VI c1131 KCN The indole-3-acetic acid derivatives wherein R is monohalo-lower alkyl are prepared from Compound VIl wherein R is benzyloxy-lower alkyl according to the following reaction:

METHOD D I omoN HzPd l CHQCN I el V (0H2)n OCHQP K -(cH, ..0H 45 Vll(a) (R =benzyloxy-lower alkyl) 1 PX:

CHCaOOCHa CHzCN CH OH I (CHQNX Hm I (CHmX l (X=chloro or bromo) VII(0) (R =hal0-l0Wer alkyl) VIII(a) V Hydrogenolysis of the benzyl group of Compound Vll(a) occurs readily in alcoholic solutions in the presence of a palladium catalyst to yield the corresponding 2-hydroxy-lower alkyl compound Vll( b). Halogenation of Vll(b) with PG, or PBr by heating to about l00-l50 C. in an inert organic solvent provides the halo-lower alkyl compound, Vll(c). Alcholysis of the nitrile Vll(c) to the ester and hydrolysis with dilute hydrochloric provides the 2-halolower alkylindole-Iiacetic acids VIll(a).

The preparation of ester derivatives of Compound VIII are performed by standard chemical syntheses well known in the art, and a detailed procedure'is included in the examples below.

The preparation of a compound wherein R is tetrazol-S-yl is described in Example 58.

EXAMPLE 1 2-Butyl-5-methylindole Step A: Preparation of N-(2,4-dimethylphenyl)pen tanamide A solution of 22.7 g. (0.188 mole) of'pentanoyl chloridein 100 ml. tetrahydrofuran is added over 20 minutes to a stirred, ice-cooled solution of 121.2 g. (1 mole) 1-amino-2,4-dimethylbenzene. After standing for several hours at room temperature the solventis removed by distillation in vacuo. The residueis taken up in ether and extracted withv 12N'HC1 to remove excess l-amino-2,4-dimethylbenzene. After washing to neutrality and drying over magnesium sulfate, the ether solution is concentrated to yield 25.1 g. of N-(2,4- dimethylphenyl)pentanamide, m.p. l l4-1 15 C.

Step B: Preparation of 2-Butyl-5-methylindole To a stirred solution of 20.5 g. (0.1 mole) of N-(2,4- dimethylphenyl)pentanamide in 250 ml. diethylaniline under nitrogen, is added in portions, 20 g. (0.526 mole) of sodamide. The mixture is heated slowly to 220 C. and maintained at this temperature for 5 hours. The reaction mixture is cooled to about 50 C., and the excess sodamide carefully decomposed by the addition of 300 ml. of water. The organic phase is extracted into 300 ml. ether and washed with portions of cold 4N l-lCl and water. The ether solution is dried and concentrated to 20.2 g. of residual solid. Recrystallization from petroleum ether gives 2-butyl-5-methylindole, m.p. 73.5-75.5 C.

Employing the procedure of Example I, but substituting for the pentanoyl chloride and the 2,4- dimethylaniline used therein equivalent amounts of an acid chloride of formula RCOCl and an aniline of structure QC H3 K described in Table I there are produced the l-R -2-R2- k -indoles also described in Table I.

V Q-omownm s-cH,

EXAMPLE 15 2-(2,2-dichloroethyl)indole Step A: Preparation of diazomethyl 2,2-dich1oroethyl ketone A solution of 3,3-dichloropropionyl chloride (1.5 g., 0.01 mole) in ether 25 ml. is added dropwise to a rapidly stirred solution of diazomethane (0.03 mole) in 25 ml. ether at -5 C. The crude product is obtained by evaporation of the solvent and excess diazomethane and used directly in the next step. Step B: Preparation of 2-(2,2-dichloroethyl)indole A mixture of 1.0 g. of diazomethyl 2,2-dichloroethyl ketone l g.- of boron trifluoride etherate and ml. of freshly distilled aniline is heated under reflux at 180 for 10 minutes. The cooled reaction mixture is treated with an excess of sodium carbonate solution and steam distilled to remove the aniline. The solid residue is collected and recrystallized from benzene-petroleum ether.

EXAMPLE 16 2-( 2,2 ,2-Trichloroethyl )indole Employing the procedure of Example 15, but substituting for the 3,3-dichloropropionyl chloride used therein an aquivalent amount of 3,3,3-trich1oropropionyl chloride, there is produced 2-(2,2,2- trichloroethyl)indo1e.

EXAMPLE 17 2-Butyl-5-methylindole-3-acetic acid Step A: Preparation of 3-(Dimethylaminomethyl)-2- butyl-S-mthylindole A solution of 6.087 g. (0.0325 mole) of 2-butyl-5- methylindole in 32.5 ml. dioxane is added dropwise to a stirred solution of 3.25 ml. of formaldehyde (25 percent aqueous), 7.15 ml. of dimethylamine (37 percent aqueous), 32.5 ml. of glacial acetic acid, and 32.5 ml. of dioxane at a temperature maintained below 0 C. After the addition is complete, the reaction mixture is allowed to warm to room temperature over a period of 18 hours. It is diluted with 300 ml. water and filtered to remove a small amount of gummy by-product. The filtrate is chilled in an ice-bath and made basic (pl-1 10- 11) with ION KOH. The precipitated product is filtered, washed with water and dried. Recrystallization from n-hexane gives 5.0 g. (63.3 percent) of 3- (dimethylaminomethyl)-2-butyl-5-methylindole, m.p.

Step B: Preparation of 2-Butyl-3-(cyanomethyl)-5- methylindole A solution of 3.42 g. (0.014 mole) of 3- dimethylaminomethyl)-5-methyl-2-butylindole dissolved in 60 ml. dry ether is added dropwise with stirring to an ice-cooled solution of 19.5 ml. of iodomethane and stirred for 6 hours at 0 C. The precipitate is filtered, washed with ether and dried to yield 4.7 g. (87 percent) of the methiodide salt of 3- (dimethylaminomethyl)-5-methyl-2-butylindole.

Without further purification, the methiodide is added to a solution of 8.93 g. potassium cyanide in 68.3

ml. of water and maintained at C. with stirring for 2 tion of 11.53 g. (0.205 mole) potassium hydroxide in 39 ml. of water and 64 ml. ethanol and refluxed for 16 hours under a blanket of nitrogen. The reaction mixture is diluted with 500 ml. water, acidified to pH 2 with concentrated hydrochloric acid and extracted with ether. The ether extract is washed with water, dried over magnesium sulfate and evaporated to a crystalline residue, 3.1 g. (90 percent). Recrystallization from petroleum ether yields 2-butyl-5-methylindole-3-acetic acid, m.p. l06l 10 C.

Employing the procedure of Example 17 as depicted by Method C, but substituting for the 2-butyl-5- methylindole used therein equivalent quantities of an indole of formula there are produced the substituted indoleacetic'acids EXAMPLE 37 2-( 2-Ch1oroethyl)indole-3-acetic acid Step A: Preparation of 2-(2-hydroxyethyl)indole-3- acetonitrile A solution of 2-(2-benzyloxyethyl)indole-3- acetonitrile (1.0 g.) obtained as an intermediate in the synthesis of the compound of Example 32 in 35 m1. of ethanol'is hydrogenated in the presence of a catalytic amount of percent palladium on carbon. After separation of the catalyst by filtration, the filtrate is concentrated to dryness, and the residue of 2-( 2- hydroxyethyl)indole-3-acetonitrile is collected and used directly in the next step. Step B: Preparation of 2-(2-chloroethyl)indole-3- acetonitrile 2-(2-Hydroxyethyl)indole-3-acetonitrile (200 mg.), phosphorus trichloride (250 mg.) and ml. of toluene are heated at reflux under nitrogen for 18 hours. The mixture is evaporated and the residue mixed with ice water and sodium carbonate. Extraction with chloroform provides the product 2-(2-chloroethyl)indole-3-acetonitrile. Step C: Preparation of methyl 2-( 2-chloroethyl)indo1e- 3-acetate An ice cold solution of 2-(2-chloroethyl)indo1e-3- acetonitrile (220 mg.) in 5 ml. of methanol containing 0.05 ml. Water is saturated with hydrogen chloride gas. After stirring at room temperature for 48 hours the solution is evaporated to dryness, and the residue treated with sodium bicarbonate solution and then extracted with methylene chloride. Purification by chromatography alumina yields methyl 2-(2-chloroethyl)indole-3-acetate. Step D: Preparation of 2-(2-chloroethy1)indo1e-3- acetic acid Methyl 2-(2-chloroethy1')indole-3-acetate 100 mg.) is hydrolyzed by refluxing in a mixture of 20 ml. benzene-10 ml. 10 percent hydrochloric acid for 3 hours. After cooling, the benzene layer is evaporated to dryness to yield 2-(2-chloroethy1)indo1e-3-acetic acid.

EXAMPLE 38 2-(2-Bromoethyl)indole-3-acetic acid Employing the process of Example 37 but substituting for the phosphorus trichloride used therein an equivalent'amount of phosphorus tribromide, there is produced 2-(2-bromoethy1)indole-3-acetic acid.

EXAMPLE 39 Methyl 5-methyl-2-propylindole-3-acetate 5-Methy1-2-propy1indole-3-acetic acid (2.776 g.) is added with stirring to a solution of acetylchloride (3 ml.) in anhydrous methanol (60 ml.) maintained at 7 C. and the resultant solution is held overnight at 0-7 C. The solution is concentrated to dryness and the residue is fractionally distilled. The distillate (b.p. l32-150/0.3 mm. Hg.) crystallizes spontaneously and is recrystallized from petroleum ether to yield 1.75 g. of methyl 5-methyl-2-propylindole-3-acetate, m.p.- 75.5"78f C.

EXAMPLE 40 Octyl 5-methyl-2-propylin dole-3-acetate 5-Methyl-2-propylindole-3-acetic acid (3.45 g., 15 mole) is stirred into mls. of n-octyl alcohol and through this mixture is bubbled dry hydrogen chloride for 3 minutes. The mixture is stirred at ambient temperature for 18 hours. Excess solvent is removed under high vacuum at a temperature below C. The oily residue is dissolved in ether, washed with water, dried over magnesium sulfate, treated with decolorizing charcoal, filtered and concentrated to dryness. The

' residue is recrystallized from a methanol-water mixture to give octyl 5-methyl-2-propy1indole-3-acetate, m.p. 35-37 C.

Employing the procedure of Example 40 but substituting for the octanol and the 5-methyl-2-propylindole-3-acetic acid utilized therein equivalent amounts of an alcohol of formula 21-] and a l-R-2-R -5(or 6)- R -indole-3-acetic acid described in Table 111, there are produced the Z 1-R-2-R -5(or 6)-R"-indo1e-3- acetates, also described in Table 111.

TABLE III cHioooH 0111002 B Q, g R l 2 R2 R i'u 1'1 m.p. EX. R R R3 z ("c.

41 1-1 n-C H H -ocil liquid 42 H n-c il, s-Cil -o-@ 74.5-76.5 43 H n-c H- H -ocll,cll oll cll liquid 44 1-1 n-C H-, s-cll, .-oc,ll liquid 45 ll n-C H s-cll, ooHi liquid 46 n-C l-i, s-cil OCH2 62.5-64.0 47 H n-C -,H-, s-cl-l -o cll, ,i-l cl-l.) 67.5-69.5 48 -ca n-C l-l, s-cll -ocll liquid 49 1-1 n-C H, s-cii oc,ll,ocl-l 50 H -(CH,),OCH, s-cl-l OCH2NO2 sl-cil,-cll=cll,n-c,li, s cll ocmol s2 -c,ll, n-C l-l, S-F -oorri 53 H -cl-l,cl=, s-cl= -o -N0i 54 H -(C1-1 SC1i 6-C1-1 o--cl- 55 cu, ii-c u, s-cmocll Q EXAMPLE 56 5-Nitro-2-propylindole-3-acetic acid A solution of sodium nitrate (11.76 g.) in concentrated sulfuric acid (300 ml.) is added dropwise with stirring to a solution of 2-propylindol-3-acetic acid (30 g.) in concentrated sulfuric acid maintained at C. in

EXAMPLE 5 7 2-Propionylindole-3-acetic acid lndole-3-acetic acid l 1.0 g.) and propionyl chloride (100 ml.) in diethyl ether (100 ml.) is added to finely powdered zinc chloride (7.0 g.) and the mixture refluxed with stirring for 1 hour. The reaction mixture is decomposed by the careful addition of water and the crude product which precipitates is filtered. Recrystallization from acetone-petroleum ether yields 4.5 g. (32 percent) of 2-propionylindole-3-acetic acid, m.p. 226-228 C.

EXAMPLE 5 8 5-(5-Methyl-2-propylindole-3-ylmethyl)tetrazole To a solution of 1.8 g. (0.0085 mole) of 3- cyanomethyl-S-methyl-2-propylindole in 20 ml. methyl cellosolve is added 1.1 g. (0.017 mole) powdered sodium azide and 0.72 g. (0.017 mole) powdered lithium chloride and the suspension refluxed and stirred for 114 hours. The solvent is removed by distillation in vacuo and the residue taken up in ether and water and treated with 12N HCl to decompose azide salts. A stream of nitrogen is bubbled through the reaction mixture to remove hydrazoic acid. The crude product which precipitates is filtered and washed with water and ether. The product is purified by dissolving in dilute sodium hydroxide and'precipitating with dilute hydrochloric acid to yield 0.5 g. of 5-(5-m'ethyl-2- propylindole-3-yl-methyl)tetrazole, m.p. l83-l84 C.

Employing the method of Example 58 but substituting for the 3-cyanomethyl-5-methyl-2-propylindole used therein, equivalent amounts of the 3- cyanomethyl-5-R -2-R -l-R-indoles described in Table IV, there are produced the 5-(5-R -2-R -l-R-- indol-3-ylmethyl)tetrazoles also described in Table IV.

OHZCN NaN Q LiCl R The active agents of the method of this invention were found in standard laboratory animals to produce myotonic symptoms consisting of temporary rigid extension of the legs when the animal is disturbed.

The compounds were initially tested for skeletal muscle stimulant properties at doses of 32 mg/kg. intraperitoneally (i.p.). Effective doses (ED were then determined for active compounds by that route, and subsequently by intravenous (i.v.) and oral (p.o.) administration.

Although toxicities were not accurately determined in all cases, no lethality was observed during the ED determinations.

The procedure used for i.p., i.v. and p.o. administrations was as follows: 0

Groups of male albino mice (Swiss strain, Canadian Breeding Laboratories), weighing 18-22 grams were employed. Compounds were suspended in 1 percent Methocel (methyl cellulose, 400 cps, 65 Hg.) with the aid of an homogenizer and administered, i.v., i.p. or p.o. in a volume of 0.2 ml/20 g. of body weight.

The results obtained following the above procedure upon the administration of the skeletal muscle stimulant agents of this invention indicate that the ED by intravenous, intraperitoneal, and oral administration are in the ranges 04-71, 07-30, 0.5-1 4 mg/kg; respectively.

It is to be noted that in so far as the active agents of this invention are concerned, no gross toxic symptoms were observed in any of the animals at the dose levels employed.

The amount of muscle stimulant agent to be employed in the method of this invention will depend upon the age, condition, weight and other factors relevant to the animal to be treated and necessarily needs .to be individualized by the physician or veterinarian for each patient. A suitable unit dosage form for oral administration is described in the following example:

EXAMPLE 65 Capsule containing 25 mgs. of active ingredient mgs./capsule Ingredient S-Methyl -2-propylindole-3-acetic acid 25 corn starch U.S.P. l0 lactose U.S.P. I30

EXAMPLE 66 Injectable preparation containing 10 mg. of active ingredient The sodium salt of 5-methyl-2-propylindole-3-acetic acid is dissolved in pyrogen free water at a concentration of 10 mg./ml. and the resulting solution is dispensed into 1 cc. pharmaceutical vials.

The soluble salts can be formed from any phar- Q maceutically acceptable materials such as sodium,

potassium, ammonia, amines, and the like. The active ingredients can also be administered in aqueous suspension as the procaine salt. In addition the active ingredients can be administered in aqueous suspension as the free acids or as the esters described herein.

What is claimed is:

l. A method of treatment of skeletal-muscle fatigability which comprises the administration to an afflicted animal of an effective amount of a skeletal muscle stimulant having the structural formula wherein R is a member selected from the group consisting of l. a carbonyl group of formula COZ wherein Z is a member selected from the group consisting of a. hydroxyl, b. lower alkoxy, c. di(lower alkyl)aminomethyl-lower alkoxy, d. hydroxy-lower alkoxy, e. phenyl-lower alkoxy, f. nitrophenyl-lower alkoxy, g. halophenyl-lower alkoxy, h. lower alkyl-phenyl-lower alkoxy, i. lower alkoxy-lower alkoxy, j. phenoxy, k. nitrophenoxy, l. halophenoxy, and m. lower alkylphenoxy, R is a member selected from the group consisting of 1. hydrogen, 2. lower alkyl, and 3. lower alkenyl; R is a member selected from the group consisting of l lower alkyl, 2. lower alkoxy-lower alkyl, 3. lower alkylthio-lower alkyl, 4. halo-lower alkyl, and 5. lower alkylcarbonyl; R is a member selected from the group consisting of 1. hydrogen, Y 2. lower alkyl, 3. halo-lower alkyl, 4. lower alkoxy-lower alkyl, 5. nitro, and

6. halo. 2. The method of claim 1, wherein the muscle stimulant has structuralformula wherein R, R and R are as defined in claim 1.

3. The method of claim 1 wherein the muscle stimulant has the structural formula CHzCHzCHa 4. The method of claim 1, wherein the muscle stim ulant has the structural formula wherein R, R R and Z are as defined in claim 1.

5. The method of'claim 1, wherein the muscle stimulant has the structural formula 0112c 0 o H V V I t; wherein R, R and R are as'defined in claim l.

6. The method of claim 1, wherein the muscle stimulant has structural formula wherein R and R are lower alkyl, and Z is as defined in claim 1.

7. The method of claim 1, wherein the muscle stimulant has the structural formula CHzCOOH J wherein R and R are as defined in claim 1.

8. The method of claim 1 wherein the muscle stimulant has structural formula OH: 0H200 Z \N [(CHzMCHa wherein Z is as defined in claim 1.

9. The method of claim 1, wherein the muscle stimulant has the formula amount of a skeletal muscle stimulant having the structural formula wherein R is a member selected from the group consisting of l. a carbonyl group of formula COZ wherein Z is a member selected from the group consisting of a. hydroxyl,

b. lower alkoxy c. d1( lower alkyl)ammomethyl-lower alkoxy,

d. hydroxy-lower alkoxy, e. phenyl-lower alkoxy,

f. nitrophenyl-lower alkoxy,

' g. halophenyl-lower alkoxy,

R is a member selected from the group consisting of 1 hydrogen, 2. lower alkyl, and 3. lower alkenyl;

R is a member selected from the group consisting of l. lowenalkyl,

2. lower alkoxy-lower alkyl, 3. lower alkylthio-lower alkyl, 4. halolower alkyl, and

5. lower alkylcarbonyl;

5 R is a member selected from the group consisting of 1. hydrogen,

2. lower alkyl,

3. halo-lower alkyl,

4. lower alkoxy-lower alkyl, 5. nitro, and

6. halo; y

and a pharmaceutically acceptable carrier. 

2. lower alkyl, and
 2. lower alkoxy-lower alkyl,
 2. The method of claim 1, wherein the muscle stimulant has structural formula wherein R1, R2 and R3 are as defined in claim
 1. 2. lower alkyl,
 2. lower alkoxy-lower alkyl,
 2. lower alkyl,
 2. lower alkyl, and
 3. lower alkenyl; R2 is a member selected from the group consisting of
 3. lower alkylthio-lower alkyl,
 3. halo-lower alkyl,
 3. The method of claim 1 wherein the muscle stimulant has the structural formula
 3. lower alkylthio-lower alkyl,
 3. lower alkenyl; R2 is a member selected from the group consisting of
 3. halo-lower alkyl,
 4. halo-lower alkyl, and
 4. The method of claim 1, wherein the muscle stimulant has the structural formula wherein R1, R2, R3 and Z are as defined in claim
 1. 4. lower alkoxy-lower alkyl,
 4. halo-lower alkyl, and
 4. lower alkoxy-lower alkyl,
 5. nitro, and
 5. lower alkylcarbonyl; R3 is a member selected from the group consisting of
 5. nitro, and
 5. The method of claim 1, wherein the muscle stimulant has the structural formula wherein R1, R2 and R3 are as defined in claim
 1. 5. lower alkylcarbonyl; R3 is a member selected from the group consisting of
 6. The method of claim 1, wherein the muscle stimulant has structural formula wherein R2 and R3 are lower alkyl, and Z is as defined in claim
 6. halo.
 6. halo; and a pharmaceutically acceptable carrier.
 7. The method of claim 1, wherein the muscle stimulant has the structural formula wherein R2 and R3 are as defined in claim
 1. 8. The method of claim 1 wherein the muscle stimulant has structural formula wherein Z is as defined in claim
 1. 9. The method of claim 1, wherein the muscle stimulant has the formula
 10. A composition for the treatment of skeletal muscle fatigability which comprises an effective amount of a skeletal muscle stimulant having the structural formula wherein R is a member selected from the group consisting of 